T helper cells that produce Interleukin-17 (IL-17) (TH17 cells) are a recently identified CD4+ T-cell subset with characterized pathological roles in autoimmune diseases1–3. The nuclear receptors retinoic acid receptor-related orphan receptors α and γt (RORα and RORγt) have indispensible roles in the development of this cell type4–7. Here we present a first-in-class, high-affinity synthetic ligand, SR1001, specific to both RORα and RORγt that inhibits TH17 cell differentiation and function. SR1001 binds specifically to the ligand binding domains (LBDs) of RORα and RORγt inducing a conformational change within the LBD that encompasses repositioning of helix 12 leading to diminished affinity for coactivators and increased affinity for corepressors resulting in suppression of the receptors transcriptional activity. SR1001 inhibited the development of murine TH17 cells as demonstrated by inhibition of IL-17A gene expression and protein production. Additionally, SR1001 inhibited the expression of cytokines when added to differentiated murine or human TH17 cells. Finally, SR1001 effectively suppressed the clinical severity of autoimmune disease in mice. Thus, our data demonstrates the feasibility of targeting the orphan receptors RORα and RORγt to specifically inhibit TH17 cell differentiation and function and indicates that this novel class of compound has potential utility in the treatment of autoimmune diseases.
Background
Alcohol use occurs across the lifespan beginning in adolescence and continuing through adulthood. Ethanol-induced pathology varies with age and includes changes in neurogenesis, neurodegeneration, and glial cell activation. Ethanol-induced changes in glial activation and immune activity are believed to contribute to ethanol-induced neuropathology. Recent studies indicate an emerging role of glial-derived neuroimmune molecules in alcohol abuse and addiction.
Methods
Adolescent and adult C57BL/6 mice were treated via gavage with 6 g/kg ethanol for 10 days and tissue was harvested one day post-treatment. We compared the effects of ethanol on chemokine and cytokine expression and astrocyte GFAP immunostaining and morphology in the hippocampus, cerebellum, and cerebral cortex.
Results
Ethanol increased mRNA levels of the chemokine CCL2/MCP-1 in all three regions of adult mice relative to controls. The cytokine IL-6 was selectively increased only in the adult cerebellum. Ethanol did not affect mRNA levels of the cytokine TNF-α in any of these brain regions in adult animals. Interestingly, CCL2, IL-6, and TNF-α mRNA levels were not increased in the hippocampus, cerebellum, or cortex of adolescent mice. Ethanol treatment of adult and adolescent mice resulted in increased GFAP immunostaining.
Conclusions
Collectively, these data indicate an age- and region-specific susceptibility to ethanol regulation of neuroinflammatory and addiction-related molecules as well as astrocyte phenotype. These studies may have important implications concerning differential alcohol-induced neuropathology and alcohol addiction across the lifespan.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.